Yves Rival - Academia.edu (original) (raw)
Papers by Yves Rival
Journal of Pharmacology and Experimental Therapeutics, Jul 23, 2004
Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and c... more Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and carbohydrates. PPAR␥ activity increases insulin sensitivity and adipocyte differentiation at the expense of adipogenesis and weight gain. The goal of this study was to 1) clone the promoter of the human adipocyte fatty acid binding protein (aP2) gene, namely fatty acid-binding protein-4, 2) characterize its pharmacological regulation, and 3) determine its putative predictability for adipogenesis. Among the selected PPAR agonists, rosiglitazone and pioglitazone displayed the highest maximal efficacy (E max) on reporter-gene assays in COS-7 cells cotransfected by either a galactosidase 4-response elementbased or a human aP2 promoter-based Luc reporter vector, along with either chimeric or full-length human PPAR expression plasmids. The non-subtype-selective 2-(4-[2-(3-[2,4-difluorophenyl]-1heptylureido)ethyl]phenoxy)-2-methyl-butyric acid (GW-2331) and the compounds [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxyl]phenoxy]-acetic acid (L-165041), (4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)-benzoic acid (GW-0072), and indomethacin behaved as partial agonists relative to pioglitazone in full-length human aP2-PPAR␥2. Beyond their partial PPAR␥ agonist properties, these compounds elicited a lower maximal up-regulation of mouse aP2 mRNA in 3T3-L1 adipocytes as compared with pioglitazone; these properties paralleled a time-dependent increase in neutral lipids. By contrast, the selective PPAR␣ agonist 2,2-dichloro-12-(4chlorophenyl)dodecanoic acid (BM-17.0744) neither stimulated the human aP2-PPAR␣ promoter reporter-gene assay, thus demonstrating a specific interaction between PPAR␥ and the aP2 promoter, nor affected lipogenesis in 3T3-L1 cells. Altogether, these data characterized a functional promoter of the human aP2 gene; its in vitro pharmacological regulation in PPAR␥-mediated reporter-gene assay may represent an interesting complement or an alternative to time-consuming procedures aiming at discriminating PPAR ligands with low lipogenic properties. Metabolic syndrome is characterized by the clustering of at least three risk factors among hypertension, certain types of dyslipidemia, impaired glucose tolerance and type II diabetes, and obesity. These metabolic abnormalities lead to atherosclerosis and related complications (Haffner and Taegtmeyer, 2003). The control of lipid and carbohydrate metabolism, including physiologic and pharmacological treatments, represents a valid rationale to reduce cardiovascular diseases in patients with metabolic syndrome (Beckman et al., 2003; Wilson and Grundy, 2003). PPARs are a subclass of the nuclear receptor superfamily acting as ligand-dependent transcription factors (Kersten et al., 2000). Three subtypes were identified; the ␣ isoform is the primary subtype expressed in liver, but also in heart and kidney, and acts as a major regulator of metabolism of fats, catabolism of fatty acids, and synthesis and catabolism of lipoproteins (Barbier et al., 2002). PPAR␣ is also involved in Parts of this work were presented as a poster at the 74th Congress of the
British Journal of Haematology, Aug 1, 1994
An efficient method for the culture of human megakaryocyte precursors in serum-free medium has be... more An efficient method for the culture of human megakaryocyte precursors in serum-free medium has been developed facilitating study of the effect of regulators of megakaryocyte growth and maturation without interference by serum-derived factors. We have investigated how megakaryocytes and their precursors respond to the procoagulant enzyme, thrombin. In addition to its already documented agonist effect on mature megakaryocytes, thrombin was found to have a marked inhibitory effect on the growth of megakaryocyte colonies from CD34' bone marrow cells stimulated by IL3. This inhibitory effect, not previously reported, was selective for megakaryocytic cells. The growth of granulomonocytic and erythroid colonies was not affected. A monoclonal antibody which neutralized the effect of exogenous transforming growth factor p (TGFP) was unable to fully neutralize the inhibitory effect of thrombin. With the use of a synthetic peptide, corresponding to the tethered thrombin receptor ligand, and of a recombinant inactive form of thrombin, we provide direct evidence that both the inhibitory effect of thrombin on megakaryocyte proliferation and its agonist effect on mature magakaryocytes are mediated by a receptor analogous to the recently cloned platelet thrombin receptor.
Atherosclerosis, May 1, 1999
Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in ... more Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in monocytes and that the C-36 peptide cleavage fragment of AAT could play a critical role in lesion progression.
Atherosclerosis, Apr 1, 2004
Atherosclerosis, Jul 1, 2000
European Urology Supplements, Mar 1, 2011
The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used fo... more The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used for the treatment of urological symptoms in benign prostatic hyperplasia (BPH). Chronic inflammation appears to be one of the key components of BPH, characterized by the presence of infiltrated T-cells and macrophages. This study aimed at determining the putative effects of Permixon on initial steps of leukocyte extravasation in a cell model of vascular inflammation. Materials & Methods: Permixon was tested in recombinant cell-based reporter gene assays to assess its PPAR-regulating effects. Its anti-inflammatory properties were evaluated in cultured human umbilical vein endothelial cells (EAhy.926). results: Fatty acids such as lauric, oleic, palmitic acids are major constituents of the hexanic extract of Serenoa repens and are also PPAR ligands; PPARα and PPARδ immuno-reactivity was described in human BPH and normal prostate tissues. The total extract and the free fatty acid fraction of Permixon elicited concentration-dependent activations of both human PPARα and PPARδ with EC50 ranging from 18-23 and 34-59 µg/ml for PPARα and PPARδ respectively. When compared to the chemical agonists of PPARα and PPARδ (fenofibric acid and GW-501516), the efficacy of Permixon was about 80% and 60%, respectively; no significant impact on PPARγ was recorded. In EAhy.926 cells, tumor necrosis factor α (TNF-α) stimulated the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1, or CD106) which is involved in T-cell and monocyte adhesion. The total extract and the free fatty acid fraction of Permixon reduced the TNF-α-stimulated expression of VCAM-1 in a concentration-dependent manner, up to 50% at 30-50 µg/ml; this effect can be related to the activation of PPARα and PPARδ which control chronic inflammation in an NFκB-dependent manner in these vascular endothelial cells. Such anti-inflammatory impact of Permixon was selective since it affected neither ICAM-1 (involved in neutrophil adhesion) nor PECAM-1 (a constitutive marker of endothelial cell). Conclusions: Several lines of evidence indicate that blood mononuclear cells are involved in the inflammatory processes at the initiation and progression of BPH; by inhibiting the expression of VCAM-1 during chronic inflammation, Permixon impedes the adherence of monocytes and T-cells to the vascular wall, and may prevent leukocyte extravasation. This new anti-inflammatory feature may explain, at least in part, the anti-inflammatory activity of Permixon.
M S-medecine Sciences, Dec 1, 2005
HAL (Le Centre pour la Communication Scientifique Directe), Nov 30, 2014
Animal study findings have revealed that individual fat depots are not functionally equivalent an... more Animal study findings have revealed that individual fat depots are not functionally equivalent and have different embryonic origins depending on the anatomic location. Mouse bone regeneration studies have also shown that it is essential to match the Hox code of transplanted cells and host tissues to achieve correct repair. However, subcutaneous fat depots from any donor site are often used in autologous fat grafting. Our study was thus carried out to determine the embryonic origins of human facial (chin) and limb (knee) fat depots and whether they had similar features and molecular matching patterns. Paired chin and knee fat depots were harvested from 11 subjects and gene expression profiles were determined by DNA microarray analyses. Adipose-derived stromal cells (ASCs) from both sites were isolated and analyzed for their capacity to proliferate, form clones, and differentiate. Chin and knee fat depots expressed a different HOX code and could have different embryonic origins. ASCs displayed a different phenotype, with chin-ASCs having the potential to differentiate into brown-like adipocytes, whereas knee-ASCs differentiated into white adipocytes. These results highlighted different features for these two fat sites and indicated that donor site selection might be an important factor to be considered when applying adipose tissue in cell-based therapies.
La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la ... more La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la reaction inflammatoire et de defense de l'organisme. Le sujet de cette these a ete d'etudier les mecanismes cellulaires de la permeabilisation de l'endothelium vasculaire. Le travail a ete centre sur la regulation de l'expression et de l'organisation de pecam-1 et de la ve-cadherine, deux proteines adhesives de la jonction endotheliale aux caracteristiques uniques. En effet, la ve-cadherine presente une distribution cellulaire restreinte a l'endothelium et pecam-1 est a l'heure actuelle la seule molecule impliquee dans la diapedese leucocytaire. La premiere partie de cette these concerne la mise au point experimentale de l'utilisation des cytokines inflammatoires a travers plusieurs tests fonctionnels. La deuxieme partie montre que l'expression de pecam-1, jusqu'a present decrite comme constitutive, peut etre regulee par les cytokines inflammatoires. La regulation negative de l'expression de pecam-1 induite par le tnf-alpha et l'ifn-gamma est couplee de plus a une forte diminution de la diapedese leucocytaire. Ces changements de synthese et d'organisation de pecam-1 constituent certainement un mecanisme de regulation de la diapedese leucocytaire. Enfin, la troisieme partie rapporte les resultats relatifs aux effets des neutrophiles sur les jonctions endotheliales. Nous avons montre que l'adherence des neutrophiles aux cellules endotheliales provoque une desorganisation du complexe ve-cadherine-catenines. Ces changements structuraux de la jonction endotheliale sont surement a l'origine de l'augmentation de permeabilite vasculaire induite par les leucocytes. Les perspectives de cette etude resident dans la determination du role de icam-1 dans la signalisation intracellulaire et dans les mecanismes d'ouverture des jonctions endotheliales. En effet, plusieurs arguments issus de la litterature laissent penser que ce recepteur, implique dans l'adherence leucocyte-cellule endotheliale, est capable apres activation d'induire des signaux intracellulaires comme la phosphorylation de proteines cytoplasmiques
Annales De Dermatologie Et De Venereologie, Dec 1, 2015
The Journal of Immunology
Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at ... more Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at inflammatory sites. Several lines of evidence show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a specific component of EC junctions, is required for leukocyte transmigration through EC monolayers. In this paper, we examined the effects of two inflammatory cytokines, TNF-alpha and IFN-gamma, on PECAM-1 and vascular endothelial-cadherin/catenin organization. We found that the addition of inflammatory cytokines (TNF-alpha plus IFN-gamma in combination, for > or = 24 h) caused PECAM-1 to disappear from EC intercellular contacts. Confocal microscopy indicated that after treatment with the cytokines, PECAM-1 was rapidly internalized. In addition, a strong inhibition of PECAM-1 synthesis and a decrease in PECAM-1 mRNA were observed. This phenomenon was only found when TNF-alpha plus IFN-gamma were used in combination. Adhesion of polymorphonuclear cells to doubly treated EC...
Skin Research and Technology, 2018
Dermal fillers are used worldwide in aesthetic medicine. Multiple technologies have been develope... more Dermal fillers are used worldwide in aesthetic medicine. Multiple technologies have been developed to provide efficient and safe injectables
Journal of Proteomics, Sep 1, 2018
Histone deacetylases (HDACs) are key enzymes involved in epigenetic modulation and were targeted ... more Histone deacetylases (HDACs) are key enzymes involved in epigenetic modulation and were targeted by HDAC inhibitors (HDACis) for cancer treatment. The action of HDACis is not restricted to histones and also prevents deacetylation of other proteins, supporting their wide biological actions. The HuT78 cell line is recognized as a key tool to support and understand cutaneous T-cell lymphoma (CTCL) biology and was used as a predictive model since HDACi such as Vorinostat and Panobinostat have both demonstrated apoptotic activities in HuT78 cells and in primary blood CTCL cells. In this study, Quisinostat (JNJ-26481585) a novel secondgeneration HDACi with highest potency for HDAC1, was tested on HuT78 cell line. Quantitative mass spectrometry (MS)-based proteomics after acetylated-lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) were used as complementary technologies to assess the modifications of the acetylated proteome. As expected, several acetylated lysines of histones were increased by the HDACi. Additional acetylated non-histone proteins were modulated after treatment with Quisinostat including the nucleolin (a major nucleolar protein), the replication protein A 70 kDa DNA-binding subunit, the phosphoglycerate kinase 1, the stress-70 protein, the proto-oncogene Myc and the serine hydroxymethyltransferase. A better knowledge of histone and non-histone acetylated protein profile after Quisinostat treatment can strongly support the understanding of non-clinical and clinical results of this HDACi. These technological tools can also help in designing new HDACis in a pharmaceutical drug discovery program. Significance: A better knowledge of histone and non-histone acetylated protein profile after HDAC inhibitors (HDACis) treatment can strongly support the understanding of non-clinical and clinical investigations in a pharmaceutical drug discovery program. Relative quantification using mass spectrometry-based proteomics after acetylated-lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) are proposed as complementary technologies to assess the modifications of the acetylated proteome. Quisinostat (JNJ-26481585) a novel second-generation HDACi with highest potency for HDAC1 was better characterized in vitro in HuT78 cells to support and understand cutaneous T-cell lymphoma (CTCL) therapeutic research program.
Atherosclerosis, 1999
Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in ... more Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in monocytes and that the C-36 peptide cleavage fragment of AAT could play a critical role in lesion progression.
![Research paper thumbnail of [Metabolic syndrome: which definition for what treatment(s)?]](https://attachments.academia-assets.com/85626497/thumbnails/1.jpg)
](Metabolic syndrome is asymptomatic and results from the increasing prevalence of obesity. Althoug... more Metabolic syndrome is asymptomatic and results from the increasing prevalence of obesity. Although several definitions exist and complicate its diagnosis, metabolic syndrome is characterized by the clustering of moderate troubles of glucose, lipid metabolism, body weight, hypertension and vascular inflammation ; the synergy between 3 of them triggers type 2 diabetes, atherosclerosis and associated clinical events. Whatever the age but particularly in adolescence, the prevalence of metabolic syndrome is high ; beyond lifestyle interventions, the available treatments address essentially a single risk factor and an unmet medical need persists. The reduction of cardiovascular events in secondary prevention has been demonstrated for some antidiabetic, hypolipidemic and antihypertensive agents but any difference in efficacy between populations with and without metabolic syndrome has yet to be established. The approval of metabolic syndrome as a specific therapeutic target would need the c...
La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la ... more La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la reaction inflammatoire et de defense de l'organisme. Le sujet de cette these a ete d'etudier les mecanismes cellulaires de la permeabilisation de l'endothelium vasculaire. Le travail a ete centre sur la regulation de l'expression et de l'organisation de pecam-1 et de la ve-cadherine, deux proteines adhesives de la jonction endotheliale aux caracteristiques uniques. En effet, la ve-cadherine presente une distribution cellulaire restreinte a l'endothelium et pecam-1 est a l'heure actuelle la seule molecule impliquee dans la diapedese leucocytaire. La premiere partie de cette these concerne la mise au point experimentale de l'utilisation des cytokines inflammatoires a travers plusieurs tests fonctionnels. La deuxieme partie montre que l'expression de pecam-1, jusqu'a present decrite comme constitutive, peut etre regulee par les cytokines inflammatoire...
European Urology Supplements, 2011
The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used fo... more The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used for the treatment of urological symptoms in benign prostatic hyperplasia (BPH). Chronic inflammation appears to be one of the key components of BPH, characterized by the presence of infiltrated T-cells and macrophages. This study aimed at determining the putative effects of Permixon on initial steps of leukocyte extravasation in a cell model of vascular inflammation. Materials & Methods: Permixon was tested in recombinant cell-based reporter gene assays to assess its PPAR-regulating effects. Its anti-inflammatory properties were evaluated in cultured human umbilical vein endothelial cells (EAhy.926). results: Fatty acids such as lauric, oleic, palmitic acids are major constituents of the hexanic extract of Serenoa repens and are also PPAR ligands; PPARα and PPARδ immuno-reactivity was described in human BPH and normal prostate tissues. The total extract and the free fatty acid fraction of Permixon elicited concentration-dependent activations of both human PPARα and PPARδ with EC50 ranging from 18-23 and 34-59 µg/ml for PPARα and PPARδ respectively. When compared to the chemical agonists of PPARα and PPARδ (fenofibric acid and GW-501516), the efficacy of Permixon was about 80% and 60%, respectively; no significant impact on PPARγ was recorded. In EAhy.926 cells, tumor necrosis factor α (TNF-α) stimulated the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1, or CD106) which is involved in T-cell and monocyte adhesion. The total extract and the free fatty acid fraction of Permixon reduced the TNF-α-stimulated expression of VCAM-1 in a concentration-dependent manner, up to 50% at 30-50 µg/ml; this effect can be related to the activation of PPARα and PPARδ which control chronic inflammation in an NFκB-dependent manner in these vascular endothelial cells. Such anti-inflammatory impact of Permixon was selective since it affected neither ICAM-1 (involved in neutrophil adhesion) nor PECAM-1 (a constitutive marker of endothelial cell). Conclusions: Several lines of evidence indicate that blood mononuclear cells are involved in the inflammatory processes at the initiation and progression of BPH; by inhibiting the expression of VCAM-1 during chronic inflammation, Permixon impedes the adherence of monocytes and T-cells to the vascular wall, and may prevent leukocyte extravasation. This new anti-inflammatory feature may explain, at least in part, the anti-inflammatory activity of Permixon.
Journal of Investigative Dermatology, 2015
Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the... more Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.
Journal of Pharmacology and Experimental Therapeutics, Jul 23, 2004
Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and c... more Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and carbohydrates. PPAR␥ activity increases insulin sensitivity and adipocyte differentiation at the expense of adipogenesis and weight gain. The goal of this study was to 1) clone the promoter of the human adipocyte fatty acid binding protein (aP2) gene, namely fatty acid-binding protein-4, 2) characterize its pharmacological regulation, and 3) determine its putative predictability for adipogenesis. Among the selected PPAR agonists, rosiglitazone and pioglitazone displayed the highest maximal efficacy (E max) on reporter-gene assays in COS-7 cells cotransfected by either a galactosidase 4-response elementbased or a human aP2 promoter-based Luc reporter vector, along with either chimeric or full-length human PPAR expression plasmids. The non-subtype-selective 2-(4-[2-(3-[2,4-difluorophenyl]-1heptylureido)ethyl]phenoxy)-2-methyl-butyric acid (GW-2331) and the compounds [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxyl]phenoxy]-acetic acid (L-165041), (4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)-benzoic acid (GW-0072), and indomethacin behaved as partial agonists relative to pioglitazone in full-length human aP2-PPAR␥2. Beyond their partial PPAR␥ agonist properties, these compounds elicited a lower maximal up-regulation of mouse aP2 mRNA in 3T3-L1 adipocytes as compared with pioglitazone; these properties paralleled a time-dependent increase in neutral lipids. By contrast, the selective PPAR␣ agonist 2,2-dichloro-12-(4chlorophenyl)dodecanoic acid (BM-17.0744) neither stimulated the human aP2-PPAR␣ promoter reporter-gene assay, thus demonstrating a specific interaction between PPAR␥ and the aP2 promoter, nor affected lipogenesis in 3T3-L1 cells. Altogether, these data characterized a functional promoter of the human aP2 gene; its in vitro pharmacological regulation in PPAR␥-mediated reporter-gene assay may represent an interesting complement or an alternative to time-consuming procedures aiming at discriminating PPAR ligands with low lipogenic properties. Metabolic syndrome is characterized by the clustering of at least three risk factors among hypertension, certain types of dyslipidemia, impaired glucose tolerance and type II diabetes, and obesity. These metabolic abnormalities lead to atherosclerosis and related complications (Haffner and Taegtmeyer, 2003). The control of lipid and carbohydrate metabolism, including physiologic and pharmacological treatments, represents a valid rationale to reduce cardiovascular diseases in patients with metabolic syndrome (Beckman et al., 2003; Wilson and Grundy, 2003). PPARs are a subclass of the nuclear receptor superfamily acting as ligand-dependent transcription factors (Kersten et al., 2000). Three subtypes were identified; the ␣ isoform is the primary subtype expressed in liver, but also in heart and kidney, and acts as a major regulator of metabolism of fats, catabolism of fatty acids, and synthesis and catabolism of lipoproteins (Barbier et al., 2002). PPAR␣ is also involved in Parts of this work were presented as a poster at the 74th Congress of the
British Journal of Haematology, Aug 1, 1994
An efficient method for the culture of human megakaryocyte precursors in serum-free medium has be... more An efficient method for the culture of human megakaryocyte precursors in serum-free medium has been developed facilitating study of the effect of regulators of megakaryocyte growth and maturation without interference by serum-derived factors. We have investigated how megakaryocytes and their precursors respond to the procoagulant enzyme, thrombin. In addition to its already documented agonist effect on mature megakaryocytes, thrombin was found to have a marked inhibitory effect on the growth of megakaryocyte colonies from CD34' bone marrow cells stimulated by IL3. This inhibitory effect, not previously reported, was selective for megakaryocytic cells. The growth of granulomonocytic and erythroid colonies was not affected. A monoclonal antibody which neutralized the effect of exogenous transforming growth factor p (TGFP) was unable to fully neutralize the inhibitory effect of thrombin. With the use of a synthetic peptide, corresponding to the tethered thrombin receptor ligand, and of a recombinant inactive form of thrombin, we provide direct evidence that both the inhibitory effect of thrombin on megakaryocyte proliferation and its agonist effect on mature magakaryocytes are mediated by a receptor analogous to the recently cloned platelet thrombin receptor.
Atherosclerosis, May 1, 1999
Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in ... more Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in monocytes and that the C-36 peptide cleavage fragment of AAT could play a critical role in lesion progression.
Atherosclerosis, Apr 1, 2004
Atherosclerosis, Jul 1, 2000
European Urology Supplements, Mar 1, 2011
The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used fo... more The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used for the treatment of urological symptoms in benign prostatic hyperplasia (BPH). Chronic inflammation appears to be one of the key components of BPH, characterized by the presence of infiltrated T-cells and macrophages. This study aimed at determining the putative effects of Permixon on initial steps of leukocyte extravasation in a cell model of vascular inflammation. Materials & Methods: Permixon was tested in recombinant cell-based reporter gene assays to assess its PPAR-regulating effects. Its anti-inflammatory properties were evaluated in cultured human umbilical vein endothelial cells (EAhy.926). results: Fatty acids such as lauric, oleic, palmitic acids are major constituents of the hexanic extract of Serenoa repens and are also PPAR ligands; PPARα and PPARδ immuno-reactivity was described in human BPH and normal prostate tissues. The total extract and the free fatty acid fraction of Permixon elicited concentration-dependent activations of both human PPARα and PPARδ with EC50 ranging from 18-23 and 34-59 µg/ml for PPARα and PPARδ respectively. When compared to the chemical agonists of PPARα and PPARδ (fenofibric acid and GW-501516), the efficacy of Permixon was about 80% and 60%, respectively; no significant impact on PPARγ was recorded. In EAhy.926 cells, tumor necrosis factor α (TNF-α) stimulated the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1, or CD106) which is involved in T-cell and monocyte adhesion. The total extract and the free fatty acid fraction of Permixon reduced the TNF-α-stimulated expression of VCAM-1 in a concentration-dependent manner, up to 50% at 30-50 µg/ml; this effect can be related to the activation of PPARα and PPARδ which control chronic inflammation in an NFκB-dependent manner in these vascular endothelial cells. Such anti-inflammatory impact of Permixon was selective since it affected neither ICAM-1 (involved in neutrophil adhesion) nor PECAM-1 (a constitutive marker of endothelial cell). Conclusions: Several lines of evidence indicate that blood mononuclear cells are involved in the inflammatory processes at the initiation and progression of BPH; by inhibiting the expression of VCAM-1 during chronic inflammation, Permixon impedes the adherence of monocytes and T-cells to the vascular wall, and may prevent leukocyte extravasation. This new anti-inflammatory feature may explain, at least in part, the anti-inflammatory activity of Permixon.
M S-medecine Sciences, Dec 1, 2005
HAL (Le Centre pour la Communication Scientifique Directe), Nov 30, 2014
Animal study findings have revealed that individual fat depots are not functionally equivalent an... more Animal study findings have revealed that individual fat depots are not functionally equivalent and have different embryonic origins depending on the anatomic location. Mouse bone regeneration studies have also shown that it is essential to match the Hox code of transplanted cells and host tissues to achieve correct repair. However, subcutaneous fat depots from any donor site are often used in autologous fat grafting. Our study was thus carried out to determine the embryonic origins of human facial (chin) and limb (knee) fat depots and whether they had similar features and molecular matching patterns. Paired chin and knee fat depots were harvested from 11 subjects and gene expression profiles were determined by DNA microarray analyses. Adipose-derived stromal cells (ASCs) from both sites were isolated and analyzed for their capacity to proliferate, form clones, and differentiate. Chin and knee fat depots expressed a different HOX code and could have different embryonic origins. ASCs displayed a different phenotype, with chin-ASCs having the potential to differentiate into brown-like adipocytes, whereas knee-ASCs differentiated into white adipocytes. These results highlighted different features for these two fat sites and indicated that donor site selection might be an important factor to be considered when applying adipose tissue in cell-based therapies.
La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la ... more La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la reaction inflammatoire et de defense de l'organisme. Le sujet de cette these a ete d'etudier les mecanismes cellulaires de la permeabilisation de l'endothelium vasculaire. Le travail a ete centre sur la regulation de l'expression et de l'organisation de pecam-1 et de la ve-cadherine, deux proteines adhesives de la jonction endotheliale aux caracteristiques uniques. En effet, la ve-cadherine presente une distribution cellulaire restreinte a l'endothelium et pecam-1 est a l'heure actuelle la seule molecule impliquee dans la diapedese leucocytaire. La premiere partie de cette these concerne la mise au point experimentale de l'utilisation des cytokines inflammatoires a travers plusieurs tests fonctionnels. La deuxieme partie montre que l'expression de pecam-1, jusqu'a present decrite comme constitutive, peut etre regulee par les cytokines inflammatoires. La regulation negative de l'expression de pecam-1 induite par le tnf-alpha et l'ifn-gamma est couplee de plus a une forte diminution de la diapedese leucocytaire. Ces changements de synthese et d'organisation de pecam-1 constituent certainement un mecanisme de regulation de la diapedese leucocytaire. Enfin, la troisieme partie rapporte les resultats relatifs aux effets des neutrophiles sur les jonctions endotheliales. Nous avons montre que l'adherence des neutrophiles aux cellules endotheliales provoque une desorganisation du complexe ve-cadherine-catenines. Ces changements structuraux de la jonction endotheliale sont surement a l'origine de l'augmentation de permeabilite vasculaire induite par les leucocytes. Les perspectives de cette etude resident dans la determination du role de icam-1 dans la signalisation intracellulaire et dans les mecanismes d'ouverture des jonctions endotheliales. En effet, plusieurs arguments issus de la litterature laissent penser que ce recepteur, implique dans l'adherence leucocyte-cellule endotheliale, est capable apres activation d'induire des signaux intracellulaires comme la phosphorylation de proteines cytoplasmiques
Annales De Dermatologie Et De Venereologie, Dec 1, 2015
The Journal of Immunology
Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at ... more Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at inflammatory sites. Several lines of evidence show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a specific component of EC junctions, is required for leukocyte transmigration through EC monolayers. In this paper, we examined the effects of two inflammatory cytokines, TNF-alpha and IFN-gamma, on PECAM-1 and vascular endothelial-cadherin/catenin organization. We found that the addition of inflammatory cytokines (TNF-alpha plus IFN-gamma in combination, for > or = 24 h) caused PECAM-1 to disappear from EC intercellular contacts. Confocal microscopy indicated that after treatment with the cytokines, PECAM-1 was rapidly internalized. In addition, a strong inhibition of PECAM-1 synthesis and a decrease in PECAM-1 mRNA were observed. This phenomenon was only found when TNF-alpha plus IFN-gamma were used in combination. Adhesion of polymorphonuclear cells to doubly treated EC...
Skin Research and Technology, 2018
Dermal fillers are used worldwide in aesthetic medicine. Multiple technologies have been develope... more Dermal fillers are used worldwide in aesthetic medicine. Multiple technologies have been developed to provide efficient and safe injectables
Journal of Proteomics, Sep 1, 2018
Histone deacetylases (HDACs) are key enzymes involved in epigenetic modulation and were targeted ... more Histone deacetylases (HDACs) are key enzymes involved in epigenetic modulation and were targeted by HDAC inhibitors (HDACis) for cancer treatment. The action of HDACis is not restricted to histones and also prevents deacetylation of other proteins, supporting their wide biological actions. The HuT78 cell line is recognized as a key tool to support and understand cutaneous T-cell lymphoma (CTCL) biology and was used as a predictive model since HDACi such as Vorinostat and Panobinostat have both demonstrated apoptotic activities in HuT78 cells and in primary blood CTCL cells. In this study, Quisinostat (JNJ-26481585) a novel secondgeneration HDACi with highest potency for HDAC1, was tested on HuT78 cell line. Quantitative mass spectrometry (MS)-based proteomics after acetylated-lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) were used as complementary technologies to assess the modifications of the acetylated proteome. As expected, several acetylated lysines of histones were increased by the HDACi. Additional acetylated non-histone proteins were modulated after treatment with Quisinostat including the nucleolin (a major nucleolar protein), the replication protein A 70 kDa DNA-binding subunit, the phosphoglycerate kinase 1, the stress-70 protein, the proto-oncogene Myc and the serine hydroxymethyltransferase. A better knowledge of histone and non-histone acetylated protein profile after Quisinostat treatment can strongly support the understanding of non-clinical and clinical results of this HDACi. These technological tools can also help in designing new HDACis in a pharmaceutical drug discovery program. Significance: A better knowledge of histone and non-histone acetylated protein profile after HDAC inhibitors (HDACis) treatment can strongly support the understanding of non-clinical and clinical investigations in a pharmaceutical drug discovery program. Relative quantification using mass spectrometry-based proteomics after acetylated-lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) are proposed as complementary technologies to assess the modifications of the acetylated proteome. Quisinostat (JNJ-26481585) a novel second-generation HDACi with highest potency for HDAC1 was better characterized in vitro in HuT78 cells to support and understand cutaneous T-cell lymphoma (CTCL) therapeutic research program.
Atherosclerosis, 1999
Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in ... more Poster presentation: Inflammation. infection and cytokines in atherosclerosis I 19 properties in monocytes and that the C-36 peptide cleavage fragment of AAT could play a critical role in lesion progression.
Metabolic syndrome is asymptomatic and results from the increasing prevalence of obesity. Althoug... more Metabolic syndrome is asymptomatic and results from the increasing prevalence of obesity. Although several definitions exist and complicate its diagnosis, metabolic syndrome is characterized by the clustering of moderate troubles of glucose, lipid metabolism, body weight, hypertension and vascular inflammation ; the synergy between 3 of them triggers type 2 diabetes, atherosclerosis and associated clinical events. Whatever the age but particularly in adolescence, the prevalence of metabolic syndrome is high ; beyond lifestyle interventions, the available treatments address essentially a single risk factor and an unmet medical need persists. The reduction of cardiovascular events in secondary prevention has been demonstrated for some antidiabetic, hypolipidemic and antihypertensive agents but any difference in efficacy between populations with and without metabolic syndrome has yet to be established. The approval of metabolic syndrome as a specific therapeutic target would need the c...
La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la ... more La migration des leucocytes a travers la barriere endotheliale constitue la premiere etape de la reaction inflammatoire et de defense de l'organisme. Le sujet de cette these a ete d'etudier les mecanismes cellulaires de la permeabilisation de l'endothelium vasculaire. Le travail a ete centre sur la regulation de l'expression et de l'organisation de pecam-1 et de la ve-cadherine, deux proteines adhesives de la jonction endotheliale aux caracteristiques uniques. En effet, la ve-cadherine presente une distribution cellulaire restreinte a l'endothelium et pecam-1 est a l'heure actuelle la seule molecule impliquee dans la diapedese leucocytaire. La premiere partie de cette these concerne la mise au point experimentale de l'utilisation des cytokines inflammatoires a travers plusieurs tests fonctionnels. La deuxieme partie montre que l'expression de pecam-1, jusqu'a present decrite comme constitutive, peut etre regulee par les cytokines inflammatoire...
European Urology Supplements, 2011
The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used fo... more The n-hexane lipidosterolic extract of Serenoa repens, namely Permixon®, has been largely used for the treatment of urological symptoms in benign prostatic hyperplasia (BPH). Chronic inflammation appears to be one of the key components of BPH, characterized by the presence of infiltrated T-cells and macrophages. This study aimed at determining the putative effects of Permixon on initial steps of leukocyte extravasation in a cell model of vascular inflammation. Materials & Methods: Permixon was tested in recombinant cell-based reporter gene assays to assess its PPAR-regulating effects. Its anti-inflammatory properties were evaluated in cultured human umbilical vein endothelial cells (EAhy.926). results: Fatty acids such as lauric, oleic, palmitic acids are major constituents of the hexanic extract of Serenoa repens and are also PPAR ligands; PPARα and PPARδ immuno-reactivity was described in human BPH and normal prostate tissues. The total extract and the free fatty acid fraction of Permixon elicited concentration-dependent activations of both human PPARα and PPARδ with EC50 ranging from 18-23 and 34-59 µg/ml for PPARα and PPARδ respectively. When compared to the chemical agonists of PPARα and PPARδ (fenofibric acid and GW-501516), the efficacy of Permixon was about 80% and 60%, respectively; no significant impact on PPARγ was recorded. In EAhy.926 cells, tumor necrosis factor α (TNF-α) stimulated the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1, or CD106) which is involved in T-cell and monocyte adhesion. The total extract and the free fatty acid fraction of Permixon reduced the TNF-α-stimulated expression of VCAM-1 in a concentration-dependent manner, up to 50% at 30-50 µg/ml; this effect can be related to the activation of PPARα and PPARδ which control chronic inflammation in an NFκB-dependent manner in these vascular endothelial cells. Such anti-inflammatory impact of Permixon was selective since it affected neither ICAM-1 (involved in neutrophil adhesion) nor PECAM-1 (a constitutive marker of endothelial cell). Conclusions: Several lines of evidence indicate that blood mononuclear cells are involved in the inflammatory processes at the initiation and progression of BPH; by inhibiting the expression of VCAM-1 during chronic inflammation, Permixon impedes the adherence of monocytes and T-cells to the vascular wall, and may prevent leukocyte extravasation. This new anti-inflammatory feature may explain, at least in part, the anti-inflammatory activity of Permixon.
Journal of Investigative Dermatology, 2015
Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the... more Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.